This invention relates to a method for the preparation and use of a bioadhesive composition.
Carboxylated polymers, such as poly(acrylic) acid, are known to be effective as bioadhesive compositions, but their use is limited owing to problems associated with mucosa irritation. To overcome these problems, it is known to blend these polymers with other materials such as starch (as described in U.S. Pat. No. 5,643,603 (Janssen Pharmaceuticals)).
Known bioadhesive compositions are described in WO 98/22097 (Bio Advances); EP 410,696 (E. R. Squibb); U.S. Pat. No. 5,643,603 (Janssen Pharmaceuticals); and U.S. Pat. No. 4,915,948 (Warner-Lambert).
WO 98/22097 refers to compositions of poly(acrylic) acid and a polar polymer or monomer produced under conditions that ensure hydrogen bonding interactions, rather than cross-linking, occur.
EP 410,696 discloses a mucoadhesive delivery system comprising poly(acrylic) acid crosslinked with 1 percent to 20 percent by weight of a polyhydroxy compound and a therapeutically effective amount of a drug. This invention is concerned with the use of low molecular weight polyhydroxy compounds.
U.S. Pat. No. 5,643,603 describes a bioadhesive carrier composition which is a tablet formulated from pregelatinized starch, synthetic polymer such as poly(acrylic) acid and a drug. The pregelatinized starch is used as a substitute adhesive allowing for lower loading of poly(acrylic) acid to reduce corresponding irritation effects.
U.S. Pat. No. 4,915,948 refers to a tablet with bioadhesive properties prepared from a blend of xanthan gum and/or a pectin combined with a solid polyol. The blend is prepared without any form of heating.
Prior art methods of crosslinking polycarboxylated polymers with polysaccharides include the method described in U.S. Pat. No. 5,895,804 (National Starch and Chemical) wherein polysaccharide and polycarboxylated polymer are combined under conditions effective to induce crosslinking of the polycarboxylated polymer.
None of the above patents or references provide a method of preparing bioadhesive compositions having the high loading of poly(acrylic) acid and corresponding adhesion and low irritation properties described in this invention.
The present invention relates to a method of producing a bioadhesive composition which comprises the steps of preparing a solution of at least one solvent and a polymer mixture wherein the polymer mixture comprises from about 10 percent by weight to about 90 percent by weight of at least one natural or synthetic polycarboxylated polymer and about 10 percent by weight to about 90 percent by weight of at least one polysaccharide; drying the solution to form a solid; and heat treating the solid at a temperature from about 60xc2x0 C. to about 200xc2x0 C. to effect cross-linking and to form the bioadhesive composition.
Any suitable aqueous or organic solvent may be used in this invention. The preferred solvent is water.
Solid, as used herein, is intended to mean a material having less than about 20 percent by weight of solvent present, and includes powders.
Solution, as used herein, is intended to mean a partial or total solubilization.
Neutralization, as used herein, may be partial or total. Such neutralization may be carried out by, but is not limited to, the use of ammonia, or any metal cations of the Group I or Group II elements of the Periodic Table.
The drying and heat treating steps may be carried out together as a one step process or individually as a two step process.
The chemistry of the natural or synthetic polycarboxylated polymer may be selected by one skilled in the art to control the degree and location of ester crosslinking.
The bioadhesive compositions produced by the method of this invention do not contain residual monomer or chemical residue, and therefore do not require a post-washing step. As the natural or synthetic polycarboxylated polymer is cross-linked to the polysaccharide backbone higher levels of natural or synthetic polycarboxylated polymer, such as poly(acrylic) acid, may be incorporated into the composition to provide good adhesion properties and low mucosa irritation.
By bioadhesive composition is meant a component that provides bioadhesive properties to a bioadhesive system in which it is included rather than, for instance, an excipient in a bioadhesive system. Bioadhesive properties mean that adhesive properties are developed on contact with animal or human mucosa, skin or body tissue or vegetable or plant tissues wherein some water or an aqueous solution is present. Typical, but non-limiting, examples of types of bioadhesives include intestinal, nasal, buccal, sub-lingual, vaginal and ocular bioadhesives. Bioadhesion compositions may be neutralized by known means.
Bioadhesion, as used herein, is intended to mean the ability of a material (synthetic or biological) to adhere to biological tissue. Bioadhesion stages can be summarized as follows. First an intimate contact must exist between the bioadhesive and the receptor tissue. Such contact results either from a good wetting of the bioadhesion surface or from the swelling of the bioadhesive. When contact is established, the penetration of the bioadhesive into the crevice of the tissue surface then takes place, or there is interpenetration of bioadhesive chains with those of the mucus, and there is formation of weak chemical bonds between entangled chains. A general description of bioadhesion may be found in the publication Bioadhesive Drug Delivery Systems, 1999, pp. 1-10, Published by Marcel Dekker.
Controlled release, as used herein, is intended to mean a method and composition for making an active ingredient available to the biological system of a host. Controlled-release includes the use of instantaneous release, delayed release, and sustained release. xe2x80x9cInstantaneous releasexe2x80x9d refers to immediate release to the biosystem of the host. xe2x80x9cDelayed releasexe2x80x9d means the active ingredient is not made available to the host until some time delay after administration. xe2x80x9cSustained Releasexe2x80x9d generally refers to release of active ingredient whereby the level of active ingredient available to the host is maintained at some level over a period of time. The method of effecting each type of release can be varied. For example, the active-ingredient can be associated physically and/or chemically with a surfactant, a chelating agent, etc. Alternatively, the active ingredient can be masked by a coating, a laminate, etc. Regardless of the method of providing the desired release pattern, the present invention contemplates delivery of a controlled-release system that utilizes one or more of the xe2x80x9creleasexe2x80x9d methods and compositions. Moreover, the present invention can be an element of the release method and/or composition, especially with respect to sustained release systems.
The bioadhesive composition of the present invention may take up and controllably release active components such as drugs. Active components may be added using any of the known methods described in the prior art, and such addition may be carried out during and/or after the production of the bioadhesive composition. Typical active components may include, but are not limited to, a therapeutic substance or a pharmaceutically active agent such as a drug, a non-therapeutic substance such as a cosmetic substance, a local or general anesthetic or pain killer, or an opiate, a vaccine, an antigen, a microorganism, a sterilizing substance, a contraceptive composition, a protein or peptide such as insulin, an insecticide, a herbicide, a hormone such as a growth hormone or a seed germination hormone, a steroid, a toxin, or a marker substance. A non-limiting list of possible active components includes hydrochlorothiazide, acetazolamide, acetylsalicyclic acid, allopurinol, alprenolol, amiloride, antiarrhythmics, antibiotics, antidiabetics, antiepileptics, anticoagulants, antimycotics, atenolol, bendroflumethiazide, benzbromarone, benzthiazide, betamethasone, bronchodilators, buphenine, bupranolol, chemotherapeutics, chlordiazepoxide, chlorquine, chloro thiazide, chlorpromazine, chlortalidone, clenbuterol, clomipramine, clonidine, co-dergocrine, cortisone, dexamethasone, dextropropoxyphene, diazepam, diazoxide, diclofenac, diclofenamide, digitalisglycoside, dihydralazine, dihydroergotamine, diltiazem, iron salt, ergotamine, ethacrynic acid, ethinylestradiol, ethoxzolamide, fenoterol, fludrocortisone, fluphenazine, fluorosemide, gallopamil, guanethidine, hormones, hydrochlorothiazide, hydrocortisone, hydroflumethiazide, immunosuppresives, ibuprofen, imipramine, indomethacine, coronartherapeutics, levodopa, lithium salt, magnesium salt, medroxyprogesteron acetate, manadione, methaqualone, 8-methoxypsoralen, methylclothiazide, methyidopa, methylprednisolone, methyltestosterone, methylthiouracil, methylxanthine, metipranolol, molsidomine, morphine, naproxen, nicergline, nifedipine, norfenefrine, oxyphenbutazone, papaverine, parmathasone, pentobarbital, perphenazine, phenobarbital, phenylbutazone, phytomenadione, pirenzepine, polythiazide, prazosine, prednisolone, prednisone, probenecid, propranolol, propylthiouracil, rescinnamine, reserpine, secbutabarbital, secobarbital, spironolactone, sulfasalazine, sulfonamide, testosterone, thioridazine, triamcinolon, triamteren, trichloromethiazide, trifluoperazine, trifluopromazine, tuberculostatic, verapamil, virustatics, zytostatics, bromocriptine, bromopride, carbidopa, carbocromen, quinine, chlorprothixene, cimetidine, clofibrat, cyclizine, desipramine, disulfiram, domperidone, doxepine, fenbufen, flufenamine acid, flunarizine, gemfibrocil, haloperidol, ketoprofen, labetalol, lorazepam, mefenamine acid, melperone, metoclopramide, nortriptyline, noscapine, oxprenolol, oxymetholone, pentazocine, pethidine, stanozolol, sulindac, sulpiride, tiotixen.
The term xe2x80x9cbioadhesive systemxe2x80x9d as used herein includes any system or product comprising the bioadhesive composition of this invention.